Journal Article

Patterns of somatic structural variation in human cancer genomes

Weischenfeldt, Joachim, Korbel, Jan O., Schumacher, Steven E., Waszak, Sebastian, Khurana, Ekta, Shapira, Ofer, Beroukhim, Rameen, Li, Yilong, Kumar, Kiran, Campbell, Peter J., Roberts, Nicola D., Haber, James E., Wala, Jeremiah A., Imielinski, Marcin

2020

Overview

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1 – 7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act. Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 631/208/211 / 631/67/69 / Basic Medicine / Cancer / Chromosome translocations / Chromosomes / Consortia / Deoxyribonucleic acid / DNA / Gene rearrangement / Gene Rearrangement - genetics / Gene sequencing / Genetic aspects / Genetic Variation / Genome, Human - genetics / Genomes / Genomic structural variations / Genomics / Health aspects / Humanities and Social Sciences / Humans / Identification and classification / Inversions / Liver cancer / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / multidisciplinary / Mutagenesis, Insertional / Mutation / Neoplasms - genetics / Replication / Reproduction (copying) / Science / Science (multidisciplinary) / Size distribution / Telomerase / Telomerase - genetics / Tumors / Variation / Whole genome sequencing